Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have, in addition to the nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), gained a definitive place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, more than thirty structurally different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 reverse transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are (or have been) in preclinical and/or clinical development [tivirapine (TIBO R-86183), loviride (alpha-APA R89439), thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097, DMP 266 (efavirenz), PETT derivatives (trovirdine, PETT-4, PETT-5) and the dichlorophenylthio(pyridyl)imidazole derivative S-1153]. The NNRTIs interact with a specific 'pocket' site of HIV-1 RT that is closely associated with, but distinct from, the NRTI binding site. NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site. However, the emergence of resistant HIV strains can be circumvented if the NNRTIs, preferably in combination with other anti-HIV agents, are used from the start at sufficiently high concentrations. In vitro, this procedure has been shown to 'knock-out' virus replication and to prevent resistance from arising. In vivo, various triple-drug combinations containing NNRTIs, NRTIs and/or PIs may result in an effective viral suppression and ensuing immune recovery. However, this so-called HAART (highly active antiretroviral therapy) may also fail, and this necessitates the design of new and more effective drugs and drug cocktails.